Edward G. Shepherd

MAPK phosphatases--regulating the immune response.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are protein phosphatases that dephosphorylate both the phosphothreonine and phosphotyrosine residues on activated MAPKs. Removal of the phosphates renders MAPKs inactive, effectively halting their cellular function. In recent years, evidence has emerged that, similar to MAPKs, MKPs are pivotal in the regulation of immune responses. By deactivating MAPKs, MKPs can modulate both innate and adaptive immunity. A number of immunomodulatory agents have been found to influence the expression of MKP1 in particular, highlighting the central role of this phosphatase in immune regulation. This Review discusses the properties, function and regulation of MKPs during immune responses.

Impact of Personalized Feeding Program in 100 NICU Infants: Pathophysiology-based Approach for Better Outcomes

Objectives: In neonatal intensive care unit infants referred for home-tube feeding methods, we evaluated the effect of an innovative diagnostic and management approach on feeding outcomes at discharge and 1 year, by comparing data from historical controls; we hypothesized that clinical and aerodigestive motility characteristics at evaluation were predictive of feeding outcomes at discharge; we assessed the economic impact of feeding outcomes. Patients and Methods: Patients (N = 100) who were referred for development of long-term feeding management strategy at 46.4 ± 13.1 weeks’ postmenstrual age were compared with 50 historical controls that received routine care. The focused approach included swallow-integrated pharyngoesophageal manometry, individualized feeding strategy, and prospective follow-up. Feeding success was defined as ability to achieve oral feedings at discharge and 1 year. Motility characteristics were evaluated in relation to feeding success or failure at discharge. Results: Higher feeding success was achieved in the innovative feeding program (vs historical controls) at discharge (51% vs 10%, P < 0.0001) and at 1 year (84.3% vs 42.9%, P < 0.0001), at a reduced economic burden (P < 0.05). Contributing factors to the innovative programs feeding success (vs feeding failure) were earlier evaluation and discharge (both P < 0.05), greater peristaltic reflex-frequency to provocation (P < 0.05), normal pharyngeal manometry (P < 0.05), oral feeding challenge success (P < 0.05), and suck-swallow-breath-esophageal swallow sequence (P < 0.05). Probability of feeding success demonstrated a prediction rate of 79.6%. Conclusions: Short-term and long-term feeding outcomes in complex neonates can be significantly improved with innovative feeding strategies at a reduced cost. Clinical and aerodigestive motility characteristics were predictive of outcomes.

An interdisciplinary bronchopulmonary dysplasia program is associated with improved neurodevelopmental outcomes and fewer rehospitalizations

Objective:Bronchopulmonary dysplasia (BPD) is a pulmonary disease associated with poor neurodevelopmental and medical outcomes. Patients with BPD are medically fragile, at high risk for complications and require interdisciplinary care. We tested the hypothesis that a chronic care approach for BPD would improve neurodevelopmental outcomes relative to the National Institute of Child and Human Development Neonatal Research Network (NICHD NRN) and reduce medical complications.Study Design:Infants were followed as inpatients and outpatients. Bayley developmental exams were carried out at 18–24 months of age and compared with the NICHD NRN report. Finally, rates of readmission (a proxy for medical complications) were compared before and after implementation of the Comprehensive Center for BPD (CCBPD).Result:Developmental scores obtained in 2007 and 2008 show that 12 and 10% of patients with moderate BPD (n=61) had Bayley Scores <70 for mental and motor indices respectively, whereas corresponding national rates were 35 and 26%. For patients with severe BPD (n=46), 15 and 11% of patients within the CCBPD vs 50 and 42% of national patients scored <70 for mental and motor indices, respectively. Finally, readmission rates dropped from 29% in the year before the implementation of the CCPD (n=269) to 5% thereafter (n=866, P<0.0001).Conclusion:The encouraging neurodevelopmental outcomes and readmission rates associated with a chronic care approach to BPD suggest these infants may be best served by a comprehensive interdisciplinary approach to care that focuses on neurodevelopment throughout the hospital stay.

Pediatric Sub-specialist Controversies in the Treatment of Congenital Heart Disease in Trisomy 13 or 18

Trisomy 13 and 18 are associated with congenital heart disease. Cardiac palliation has been reported in the literature, but is not usually done in this population. Thus, a multi-disciplinary team may experience controversy in formulating a care plan that includes cardiac intervention. Our objective was to determine differences in recommendations for cardiac intervention in this population between physicians specializing in pediatric cardiac critical care, neonatology, and genetics. A web-based survey was performed between April 2007 and August 2008. This survey evaluated surgical and transcatheter cardiac palliations that had been performed for individuals with trisomy 13 or 18 at the respondent’s institution, the respondent’s recommendations for cardiac intervention in hypothetical symptomatic patients with trisomy 13 or trisomy 18 and the influence of parental preference on these recommendations. Eight hundred fifty-nine responses were obtained from a primarily academic practice setting (59%). Cardiologists were most likely to recommend intervention; low risk interventions were recommended by 32% of cardiologists, 7% of neonatologists and 20% of geneticists. Parental request to intervene resulted in a 3 fold increased in the likelihood of all specialist recommending intervention. Counseling of families frequently occurred by multiple sub specialists (50%) and there was frequently (71%) a difference in opinion. Individuals with trisomy 13 or 18 are receiving cardiac intervention at many institutions. Cardiologists were more likely than geneticists or neonatologists to recommend intervention on all heart lesions other than single ventricle palliation which no specialists recommended. Parental wishes that “everything be done” significantly influenced all specialists’ recommendations.

Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia

Recommended Citation Abman, S. H., Collaco, J. M., Shepherd, E. G., Keszler, M., Cuevas-Guaman, M., Welty, S. E., Truog, W. E., McGrath-Morrow, S. A., Moore, P. E., Rhein, L. M., Kirpalani, H., Zhang, H., Gratny, L. L., Lynch, S. K., Curtiss, J., Stonestreet, B. S., McKinney, R. L., Dysart, K. C., Gien, J., Baker, C. D., Donohue, P. K., Austin, E., Fike, C., Nelin, L. D., . Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. The Journal of pediatrics 181, 12-28 (2017).

Tracheostomy placement in infants with bronchopulmonary dysplasia: safety and outcomes.

Optimizing the timing and safety for the placement of a tracheostomy in infants with bronchopulmonary dysplasia (BPD) has not been determined. The purpose of the present study was to describe the data from a single institution about the efficacy and safety of tracheostomy placement in infants with BPD needing long‐term respiratory support. We established a service line for the comprehensive care of infants with BPD and we collected retrospective clinical data from this service line. We identified patients that had a trachostomy placed using the local Vermont‐Oxford database, and obtained clinical data from chart reviews. We identified infants who had a tracheostomy placed for the indication of severe BPD only. Safety and respiratory efficacy was assessed by overall survival to discharge and the change in respiratory supportive care from just before placement to 1‐month post‐placement. Twenty‐two patients (750 ± 236 g, 25.4 ± 2.1 weeks gestation) had a tracheostomy placed on day of life 177 ± 74 which coincided with a post‐conceptual age of 51 ± 10 weeks. At placement these infants were on high settings to support their lung disease. The mean airway pressure (MAP) was 14.3 ± 3.3 cmH2O, the peak inspiratory pressure was 43.7 ± 8.0 cmH2O, and the FiO2 was 0.51 ± 0.13. The mean respiratory severity score (MAP × FiO2) 1 month after tracheostomy was significantly (P = 0.03) lower than prior to tracheostomy. Survival to hospital discharge was 77%. All patients with tracheostomies that survived were discharged home on mist collar supplemental oxygen. In conclusion, the high survival rate in these patients with severe BPD and the decreased respiratory support after placement of a tracheostomy suggests that high ventilatory pressures should not be a deterrent for placement of a tracheostomy. Future research should be aimed at determining optimal patient selection and timing for tracheostomy placement in infants with severe BPD. Pediatr Pulmonol. 2013; 48:245–249.

Respiratory severity score on day of life 30 is predictive of mortality and the length of mechanical ventilation in premature infants with protracted ventilation

We tested the hypothesis that Respiratory Severity Score (RSS) on day of life 30 is predictive of mortality and length of mechanical ventilation in premature infants on prolonged mechanical ventilation.

In Vitro Evaluation of Radio-Labeled Aerosol Delivery Via a Variable-Flow Infant CPAP System

BACKGROUND: Nasal CPAP is widely used in neonatal ICUs. Aerosolized medications such as inhaled steroids and β agonists are commonly administered in-line through nasal CPAP, especially to infants with bronchopulmonary dysplasia. We hypothesized that aerosol delivery to the lungs via variable-flow nasal CPAP in an in vitro model would be unreliable, and that the delivery would depend on the position of the aerosol generator within the nasal CPAP circuit. METHODS: We used a system that employed a test lung placed in a plastic jar and subjected to negative pressure. Simulated inspiration effort was measured with a heated-wire anemometer. We used technetium-99m-labeled diethylene triamine penta-acetic acid as our aerosol. The nebulizer was placed either close to the humidifier or close to the nasal prongs in the circuit, and patient effort was simulated with a minute ventilation of 0.4 L/min. RESULTS: Relative aerosol delivery to the infant test lung with the nebulizer close to the humidifier was extremely low (0.3 ± 0.4%), whereas placing the nebulizer close to the nasal prongs resulted in significantly (P < .001) improved delivery (21 ± 11%). Major areas of aerosol deposition with the nebulizer close to the humidifier versus close to the nasal prongs were: nebulizer (10 ± 4% vs 33 ± 13%, P < .001), exhalation limb (9 ± 17% vs 26 ± 30%, P = .23), and generator tubing (21 ± 11% vs 19 ± 20%, P = .86). Placing the nebulizer close to the humidifier resulted in 59 ± 8% of the aerosol being deposited in the inhalation tubing along the heater wire. CONCLUSIONS: Isotope delivery from an aerosol generator placed near the humidifier on variable-flow nasal CPAP was negligible in this in vitro setup; however, such delivery was significantly improved by locating the aerosol generator closer to the nasal CPAP interface.

Early extubation attempts reduce length of stay in extremely preterm infants even if re-intubation is necessary

OBJECTIVE Prolonged mechanical ventilation in the extremely premature infant is associated with the development of bronchopulmonary dysplasia (BPD). Clinically, the decision to extubate the extremely low birth weight (ELBW) infant can be difficult. There is continued debate regarding whether it is better for an ELBW infant to remain on the ventilator or to extubate to nasal constant positive airway pressure (nCPAP). It has also been argued that repeated intubations may be detrimental to ELBW infants. We tested the hypothesis that earlier extubation attempts would decrease length of hospital stay and BPD. STUDY DESIGN A database maintained on infants born at <27 completed weeks gestation admitted to our all referral NICU for a 36 month period was queried (n = 224). RESULTS Day of life (DOL) of the first extubation attempt was inversely correlated with birth weight (p <  0.001) and gestational age (p <  0.01). The DOL of the 1st extubation attempt correlated with the need for re-intubation (p <  0.001), but not with mortality (p = 0.27). In survivors, earlier DOL of 1st extubation attempt was associated with shorter LOS (p <  0.001). Earlier DOL of the 1st extubation attempt was associated with less need for supplemental oxygen (p <  0.001) at 36 weeks CGA, while re-intubation was not (p = 0.50). CONCLUSION In our cohort of extremely premature infants, the earlier the first extubation attempt the sooner the patient was discharged home and the less likely to develop BPD. Our study suggests that extubation should not be delayed in extremely premature infants due to fears of need for re-intubation.

Skin Rounds: A Quality Improvement Approach to Enhance Skin Care in the Neonatal Intensive Care Unit.

Background:Skin injuries are common among neonatal intensive care unit (NICU) patients and may lead to significant complications. Standardized methods of preventing, detecting, and treating skin injuries are needed. Purpose:The aim of this project was to standardize the assessment, documentation, and tracking of skin injuries among hospitalized neonatal patients and to determine the incidence of pressure ulcers in this patient population. Methods:(1) Creation of an interdisciplinary skin team to identify skin injuries through weekly skin rounds. (2) Assessment of all patients at least twice daily for the presence of skin injuries. Interventions were implemented upon identification of a skin injury. Pressure ulcers of Stage II or more were further assessed by wound/ostomy nurses. Findings:A total of 2299 NICU patients were hospitalized and assessed between July 2011 and December 2015. After the initiation of skin rounds, the baseline incidence of pressure ulcers increased from 0.49 per 1000 patient days to 4.6 per 1000 patient days, reflecting an improvement in detection and reporting. The most common skin injuries detected included erythema, skin tears, and ecchymosis; the most common cause of injuries was medical devices. Implications for Practice:A dedicated skin team can improve the detection and reporting of skin injuries among NICU patients. Determination of the incidence of pressure ulcers in this population is critical to develop targeted interventions. Implications for Research:Further research is needed to determine the most effective interventions to prevent and treat skin injuries among hospitalized neonates.